Abnormal airway constriction is an important feature of asthma. Much research has been focused on the activation cascade from receptor activation to contraction in airway smooth muscle. This proposal takes the alternative approach to investigate the biological feedback (mechanosensitive modulation) by which muscle shortening leads to airway smooth muscle inactivation as depicted below. Smooth Muscle Cell Activation <---- Receptor Activation to to Smooth Muscle Cell Shortening Decrease in Muscle Length The specific cellular processes that are inactivated by muscle shortening include phosphatidylinositol turnover, cytosolic [Ca2+], and myosin light chain phosphorylation. The following five specific aims are designed to investigate this biological feedback mechanistically and systematically. l. Determination of the site of mechanosensitive modulation. 2. Determination of receptor-selectivity in mechanosensitive modulation. 3. Characterization of the pharmacodynamics of mechanosensitive modulation. 4. Determination of the feedback signal in mechanosensitive modulation. 5. Characterization of the differential regulation of force generation and shortening capacity. These specific aims are fundamental to the long-term goal of understanding mechanosensitive modulation at the molecular level. The hope is that understanding this biological feedback mechanism may offer a new way of controlling airway smooth muscle activation and therefore airway resistance.